- Some intramolecular rearrangements when pentofuranoses are treated with diethylaminosulphur trifluoride (DAST)
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Treatment of methyl 2,3-O-isopropylidene-β-D-ribofuranoside with DAST gave a good yield of 2,3-O-isopropylidene-5-O-methyl-β-D-ribofuranosyl fluoride in which the methoxy group had migrated from C-1 -> C-5 and been replaced with retention of configuration by fluorine.The corresponding aldehyde when treated under similar conditions underwent a similar migration to give 5-deoxy-5-fluoro-2,3-O-isopropylidene-5-O-methyl-β-D-ribofuranosyl fluoride.A similar migration occurred with methyl 2',3'-di-O-acetyl-β-D-ribofuranoside and with acetyl 2,3-O-isopropylidene-D-ribofuranose but not with 1,2,3-tri-O-acetyl-D-ribofuranose.Thus the migration depends upon the migratory aptitude of the substituent at C-1 and the conformation of the furanose ring.Two ribofuranosyl fluorides were used as starting materials from which to make nucleosides by the method of Noyori and Hayoshi.
- Lloyd, A. E.,Coe, P. L.,Walker, R. T.,Howarth, O. W.
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Read Online
- Selective cleavage of 2,3-O-isopropylidene group: A case of anchimeric assistance from O-glycoside
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Alkyl 2,3-O-isopropylidene-5-O-methoxymethylfuranoside derivatives undergo selective cleavage of the 2,3-O-isopropylidene group, if oriented cis to the O-glycoside, in the presence of trifluoroacetic acid. Otherwise, the cleavage of the 5-O-methoxymethyl group is favoured over the 2,3-O-isopropylidene group.
- Wakharkar, Radhika D.,Sahasrabuddhe, Manjusha B.,Borate, Hanumant B.,Gurjar, Mukund K.
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Read Online
- The reaction of O-isopropylidene pentodialdo-1,4-furanoses with lithium diisopropylamide
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Three O-isopropylidene group-protected pentose aldehydes (methyl 2,3-O-isopropylidene-β-D-ribo-pentodialdo-1,4-furanoside (1), methyl 2,3-O-isopropylidene-α-D-lyxo-pentodialdo-1,4-furanoside (2), and 3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose (3)) were treated at -30°C with lithium diisopropylamide (LDA) and the mixtures obtained were reduced with LiAlH4. The products, obtained in moderate yields, proved that deacetonation occurred followed by aldol reactions between aldehydes 1-3 and acetone. Copyright (C) 1999 Elsevier Science Ltd.
- Stepowska, Halszka,Zamojski, Aleksander
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Read Online
- The quaternization reaction of 5-o-sulfonates of methyl 2,3-o-isopropylidene-β-D-ribofuranoside with selected heterocyclic and aliphatic amines
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The synthesis of N-((methyl 5-deoxy-2,3-O-isopropylidene-β-D-ribofuranoside)-5-yl) ammoniumsalts are presented. To determine the effect of the nucleophile type and outgoing group on the quaternization reaction, selected aliphatic and heterocyclic aromatic amines reacted with: methyl 2,3-O-isopropylidene-5-O-tosyl-β-D-ribofuranoside or methyl 2,3-O-isopropylidene-5-O-mesyl-β-D -ribofuranoside ormethyl 2,3-O-isopropylidene-5-O-triflyl-β-D-ribofuranosidewere performed on amicro scale. High-resolution 1H- and 13C-NMRspectraldata for all newcompoundswere recorded. Additionally, the single-crystalX-raydiffraction analysis formethyl 2,3-O-isopropylidene-5-O-mesyl-β-D-ribofuranoside and selected in silico interaction models are reported.
- ?lusarz, Rafa?,Chojnacki, Jaros?aw,Dmochowska, Barbara,Madaj, Janusz,Samaszko-Fiertek, Justyna
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Read Online
- Sugar vanadates: Synthesis and characterisation of mannopyranoside and ribofuranoside esters incorporating VO3+
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The sugars, methyl 4,6-di-O-methyl-α-D-mannopyranoside (H2m) and methyl 5-O-methyl-β-D-ribofuranoside (H2r) have been synthesized. These react smoothly with [VIVO(L)(H2O)] in methanol in air affording the dark coloured vanadates [VvO(Hm)(L)] and [VvO(Hr)(L)] in excellent yields (L2- = N-salicylideneglycinate). The crystal structure determination of [VvO(Hm)(L)] revealed five-membered chelation of VO3+ by the alcoholic and alkoxide oxygen atoms of the monoionised carbohydrate. The two atoms lie respectively trans to the oxo oxygen and aldimine nitrogen atoms. The five V-O bonds are unequal and span the range 1.57-2.37 A. The asymmetric unit of the complex consists of two metrically similar molecules locked in carboxylate-alcohol O ... O hydrogen bonding generating a macrocyclic cavity. In solution each ester displays a single 51V resonance near δ -544. The 1H NMR parameters of the alkoxidic and alcoholic CH protons and of OMe protons are consistent with the O,O-chelation mode for both the vanadates.
- Rajak, Kajal Krishna,Rath, Sankar Prasad,Mondal, Sujit,Chakravorty, Animesh
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Read Online
- Increasing the H+ exchange capacity of porous titanium phosphonate materials by protecting defective P-OH groups
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Hierarchically macro-/mesoporous titanium phosphonates with enlarged H + exchange capacity were synthesized in the presence of a series of alkyl amines that acted as protective groups for the defective P-OH, which were used as promising solid acid catalysts to replace conventional liquid acid catalysts and acidic resins in some acid-catalytic reactions.
- Ma, Tian-Yi,Liu, Lei,Deng, Qing-Fang,Lin, Xiu-Zhen,Yuan, Zhong-Yong
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Read Online
- BIOMARKER PANEL TARGETED TO DISEASES DUE TO MULTIFACTORIAL ONTOLOGY OF GLYCOCALYX DISRUPTION
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The present disclosure provides biomarkers useful as companion diagnostics for detecting glycocalyx-based disease that is amenable to treatment using compounds designed for improving the condition of the glycocalyx and/or reducing inflammation and/or oxidative damage, as well as related compositions, kits, and methods.
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- MEAYAMYCIN ANALOGUES AND METHODS OF USE
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Compounds according to formula (I), where R is as defined herein, have anti-cancer properties.
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Page/Page column 5
(2021/10/15)
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- Conversion of: N- acyl amidines to amidoximes: A convenient synthetic approach to molnupiravir (EIDD-2801) from ribose
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An efficient method is described for the preparation of molnupiravir (EIDD-2801) an antiviral agent via regioselective conversion of an N-acyl-nucleoside intermediate, generated through stereo and regioselective glycosylation of protected ribose and N4-acetyl cytosine, to an amidoxime. This method avoids use of expensive starting materials, enzymes, complex reagents, and cumbersome purification procedures.
- Ahmed, Ajaz,Ahmed, Qazi Naveed,Mukherjee, Debaraj
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p. 36143 - 36147
(2021/12/04)
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- A facile ultrasound-assisted synthesis of methyl 2,3-O-isopropylidene-β-D-ribofuranoside from D-ribose and its use to prepare new 1,2,3-triazole glycoconjugates
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The conversion of D-ribose into its 2,3-O-isopropylidene derivative using ultrasonic irradiation is described. The ultrasound proved to be an excellent alternative as the energy source for the reaction. Different reaction times were investigated, and shorter reaction times and high yield were achieved without the need for purification of the acetonide. The compound was then applied as the starting material in the synthesis of 23 new glycoconjugates of 1,2,3-triazole that are tethered together in different ways. The synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR, and HRMS techniques.
- Evangelista, Tereza Cristina Santos,Aquino, Gabriel Alves Souto de,Donza, Marcio Roberto H.,Leit?o, Rafael Lisboa,Carvalho, Victor Salarolli de,Kaiser, Carlos Roland,Ferreira, Sabrina Baptista
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p. 243 - 268
(2021/10/23)
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- Structure-property relationships of ribose based ionic liquids
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The authors of this work have successfully synthesized a broad choice of new ribose based ionic liquids, using several varying protecting groups (methyl, ethyl, allyl and benzyl) at the various positions of the carbohydrate, as well as different quarternised N-heterocycles and different anions. These consistent variations of the carbohydrate based ionic liquids (CHILs) enabled an extensive structure-property relationship study of thermal properties, allowing the authors to prove existing trends and to find a correlation between the decomposition temperature and the structure of the CHILs.
- Jopp, Stefan,Komabayashi, Mirai,Stiller, Tanja
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- Tumor immunity compound and application thereof
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Disclosed are a tumor immunity compound and an application thereof. The invention discloses a compound as shown in the formula (I), optical isomers thereof, and pharmaceutically acceptable salts thereof, and an application of the compound as an STING agonist.
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Paragraph 0662; 0663-0667
(2020/07/14)
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- Preparation method of ticagrelor key intermediate iodide
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The invention discloses a preparation method of ticagrelor key intermediate iodide, which comprises the following steps of: (1) synthesis of an intermediate 1: taking D-ribose as a raw material, methanol and acetone as solvents, adding thionyl chloride as a catalyst, and concentrating to remove the solvents after the reaction is finished, so as to obtain the intermediate 1, and (3) synthesis of the key intermediate iodide: by taking acetonitrile as a solvent, adding the intermediate 1 and sodium iodide into a reaction system, dropwise adding trimethylchlorosilane, adding a small amount of water for quenching reaction after the reaction is finished, evaporating to remove acetonitrile, extracting with the solvent, and concentrating to obtain the key intermediate iodide. According to the preparation method of the ticagrelor key intermediate iodide, in the synthesis process of the intermediate 1, thionyl chloride is adopted to replace hydrochloric acid to serve as a catalyst, the reactionconversion rate is greatly increased, then trimethylchlorosilane/sodium iodide serves as an iodinating agent, the reaction condition is mild, aftertreatment is simple, and the conversion rate is high.
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Paragraph 0038-0043
(2020/05/01)
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- Total Synthesis of Meayamycin and O-Acyl Analogues
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A short, scalable total synthesis of meayamycin is described by an approach that entails a longest linear sequence of 12 steps (22 steps overall) from commercially available chiral pool materials (ethyl l-lactate, BocNH-Thr-OH, and d-ribose) and introduces the most straightforward preparation of the right-hand subunit detailed to date. The use of the approach in the divergent synthesis of a representative series of O-acyl analogues is exemplified.
- Boger, Dale L.,Chanda, Prem B.,Chowdari, Naidu S.,Gangwar, Sanjeev,Gartshore, Christopher,Momirov, Jelena,Sarkar, Anindya,Tadano, Shinji,Vite, Gregory D.,Zhang, Qian
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- Industrial large-scale production method of capecitabine intermediate
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The invention provides an industrial large-scale production method of a capecitabine intermediate. The industrial large-scale production method adopts a one-pot production method of simultaneously adding methanol and acetone, and is a preparation method which is energy-saving, short in production period and high in yield; a method of adding low-boiling-point solvents such as ethyl acetate into dimethyl sulfoxide or pyrrolidone for reflux cooling to take away heat is adopted; and a production method of hydrolyzing while distilling is designed, the methanol and the acetone which are generated byhydrolysis are distilled out, the methanol and the acetone in water are continuously reduced, the reaction is carried out towards K3, and the reaction is complete and thorough.
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Paragraph 0041; 0042
(2020/09/20)
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- PRMT5 INHIBITORS
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The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts thereof, which are PRMT5 inhibitors.
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Page/Page column 35; 47-48
(2020/03/02)
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- New glycosylated platinum(II) phthalocyanine containing ribose moiety – synthesis and photophysical properties
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The synthesis and spectral characterisation of new glycoconjugated phthalonitrile connected with triazole linker via Cu(II)-mediated click reaction is reported. Treatment of azido derivative of 1-methoxy-2,3- O-isopropylidene-β-D-ribose with 4-O-propargyloxy-substituted phthalonitrile in presence copper(II) sulfate pentahydrate and sodium L-ascorbate in tert-butanol/water gave desired glycophthalonitrile with 84% yield. This precursor underwent mixed-cyclisation with the tert-butyl-substituted phthalonitrile, to afford the mono-glycosylated A3B-type platinum(II) phthalocyanine. Upon irradiation this compound could sensitise the formation of singlet oxygen in acetone, with 0.95 quantum yield by comparative method with use of 1,3-diphenylisobenzofuran (DPBF) as scavenger.
- Burtsev, Ivan D.,Volov, Alexander N.
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- NOVEL SPIROBICYCLIC ANALOGUES
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The present invention relates to novel spirobicyclic analogues of Formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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Page/Page column 59-60
(2019/06/23)
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- Computer Modelling and Synthesis of Deoxy and Monohydroxy Analogues of a Ribitylaminouracil Bacterial Metabolite that Potently Activates Human T Cells
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5-(2-Oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) is a natural product formed during bacterial synthesis of vitamin B2. It potently activates mucosal associated invariant T (MAIT) cells and has immunomodulatory, inflammatory, and anticancer properties. This highly polar and unstable compound forms a remarkably stable Schiff base with a lysine residue in major histocompatibility complex class I–related protein (MR1) expressed in antigen-presenting cells. Inspired by the importance of the ribityl moiety of 5-OP-RU for binding to both MR1 and the T cell receptor (TCR) on MAIT cells, each OH was removed in silico. DFT calculations and MD simulations revealed a very stable hydrogen bond between the C3′?OH and uracil N1H, which profoundly restricts flexibility and positioning of each ribityl-OH, potentially impacting their interactions with MR1 and TCR. By using deoxygenation strategies and kinetically controlled imine formation, four monodeoxyribityl and four monohydroxyalkyl analogues of 5-OP-RU were synthesised as new tools for probing T cell activation mechanisms.
- Ler, Geraldine J. M.,Xu, Weijun,Mak, Jeffrey Y. W.,Liu, Ligong,Bernhardt, Paul V.,Fairlie, David P.
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p. 15594 - 15608
(2019/11/16)
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- Preparation process for L-lyxose
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The invention belongs to the technical field of L-lyxose preparation, and relates in particular to a preparation process for L-lyxose. The preparation process comprises the following steps: synthesisofzing 1-methyl-D-ribose, synthesis of 2,3-propylidene-methyl-D-ribose, synthesis of 2,3-propylidene-methylsulfonyl-mthyl-D-ribose, and synthesis of 2,3-propylidene-methyl-L-lyxose and L-lyxose. Thepreparation process for the L-lyxose takes D-ribose as the raw material, and is used for synthesizing L-lyxose by methyl conversion, propylidene conversion, protective group (methylsulfonyl) conversion, and conversion de-protection, so that L-lyxose is prepared through D to L conversion and methyl and propylidene desorption. The whole preparation process is high in catalysisconversion efficiency,is relatively simple in process, adopts cheap and easily available raw materials, is simple and convenient to operate, and is safe; and the obtained product is high in purity.
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Paragraph 0024; 0027; 0031; 0034; 0038; 0041
(2019/02/25)
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- Adenosine diphosphate ribose compound, preparation method and biological activity thereof
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The invention discloses an adenosine diphosphate ribose compound, which has a general formula shown as (I), wherein the definitions of all substituents are detailed in the specification. In addition,the invention also discloses a preparation method and application of the compound. The adenosine diphosphate ribose (ADPR) structural analogue provided by the invention has specific TRPM2 (transient receptor potential melastatin 2) inhibitory activity.
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Paragraph 0115-0119
(2019/01/24)
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- A novel and environmental friendly synthetic route for hydroxypyrrolidines using zeolites
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A critical step in the synthesis of the hydroxypyrrolidines, 1,4-dideoxy-1,4-imino-L-lyxitol and 1,4-dideoxy-1,4-imino-D-lyxitol, from the corresponding D-sugars is the synthesis of O-methyl 2,3-O-isopropylidenepentofuranoses. Instead of applying homogeneous catalysis process with conventional inorganic acid catalysts like HCl and HClO4, it was found that heterogeneous catalysis using zeolites could be used for the one-pot synthesis of O-methyl 2,3-O-isopropylidenepentofuranoses directly from D-sugars, MeOH and acetone at mild condition. The best catalyst was H-beta zeolite containing a Si/Al molar ratio of 150, where a yield of >83% was obtained. The overall yields of the five-step procedure to 1,4-dideoxy-1,4-imino-L-lyxitol and 1,4-dideoxy-1,4-imino-D-lyxitol were 57% and 50%, respectively. This synthetic procedure has several advantages such as competitive overall yield, reduced number of steps, and mild reaction conditions. Furthermore, the zeolite catalyst can be easily recovered from the reaction mixture and reused with no loss of activity.
- Fan,Chuah,Jaenicke, Stephan
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p. 103 - 114
(2018/12/13)
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- Preparation method of capecitabine intermediate
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The invention discloses a preparation method of a capecitabine intermediate 1, 2, 3-O-triacetyl-5-deoxy-D-furanoside, which belongs to the technical field of medicinal chemistry. According to the invention, D-ribose (a compound I) is used as an initial raw material, and is subjected to a protective group reaction with methanol and acetone under the catalysis of solid acid, 1, 2, 3-hydroxyl is protected to obtain a compound II, then the compound II and thionyl chloride are subjected to a chlorination reaction, hydroxymethyl is changed into chloromethyl, a compound III is obtained, the compoundIII is subjected to a reduction reaction through platinum/carbon catalytic hydrogenation to obtain a compound IV, the compound IV is subjected to acidic hydrolysis to obtain a compound V, and the compound V is subjected to acetylation to obtain a target compound VI. The whole process is short in reaction step and high in economy; side reactions are few, and product purity is high; no wastewater isgenerated in the first three steps, so that the method is more environment-friendly; and the method is beneficial to industrial production of the capecitabine intermediate 1, 2, 3-O-triacetyl-5-deoxy-D-furanoside.
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Paragraph 0007; 0016-0017
(2019/12/02)
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- AMPHIPHILE PRODRUGS
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Amphiphilic prodrugs of general formula A-X are disclosed, wherein A is a biologically active agent or may be metabolised to a biologically active agent; and X is selected from the group consisting of R, or up to three R moieties attached to a linker, Y1, Y2 or Y3, wherein R is selected from a group consisting of alkyl, alkenyl, alkynyl, branched alkyl, branched alkenyl, branched alkynyl, substituted alkyl, substituted alkenyl and substituted alkynyl groups and their analogues; Y1 is a linker group which covalently attached to an R group at one site and is attached to A at a further independent site; Y2 is a linker group which is covalently attached to two R groups at two independent sites and is attached to A at a further independent site; and Y3 is a linker group which is covalently attached to three R groups at three independent sites and is attached to A at a further independent site. Self-assembly of the amphiphilic prodrugs into reverse lyotropic phases, particularly hexagonal, cubic and sponge, is disclosed. In preferred embodiments A is dopamine or a 5-fluorouracil prodrug.
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Paragraph 0142; 0143; 0144
(2019/06/12)
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- Preparation method of high-purity capecitabine key intermediate
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The invention discloses a preparation method of a high-purity capecitabine key intermediate. The preparation method comprises the following steps: taking D-ribose as an initial raw material, performing hydroxyl protection, 5-site tosylation, reduction, deprotection and acetylation to obtain high-purity 1,2,3-O-triacetyl-5-deoxo-D-ribose, wherein the 5-site tosylation reaction is carried out in anorganic solvent 1 by adopting inorganic base 1. Meanwhile, the acetylation reaction is carried in the presence of alkali 2 by taking water as a reaction solvent and taking 4-dimethylamiopryidine as acatalyst. The preparation method disclosed by the invention is mild in reaction conditions, high in yield, economic and effective, the purity of the prepared 1,2,3-O-triacetyl-5-deoxo-D-ribose can reach 99.0%, the alpha-isomer is small in content even is not detected, and the preparation method is applicable to large-scale industrial production.
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Paragraph 0043; 0044; 0045
(2019/03/06)
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- Visible-Light-Mediated, Chemo- and Stereoselective Radical Process for the Synthesis of C-Glycoamino Acids
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An approach for efficient synthesis of C-glycosyl amino acids is described. Different from typical photoredox-catalyzed reactions of imines, the new process follows a pathway in which α-imino esters serve as electrophiles in chemoselective addition reactions with nucleophilic glycosyl radicals. The process is highlighted by the mild nature of the reaction conditions, the highly stereoselectivity attending C-C bond formation, and its applicability to C-glycosylations using both armed and disarmed pentose and hexose derivatives.
- Ji, Peng,Zhang, Yueteng,Wei, Yongyi,Huang, He,Hu, Wenbo,Mariano, Patrick A.,Wang, Wei
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supporting information
p. 3086 - 3092
(2019/05/01)
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- Synthesis of N-alkyl substituted iminosugars from D-ribose
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An effective and facile method for the synthesis of N-alkylated hydroxylpyrrolidine and hydroxylpiperidine is described. A number of N-alkyl substituted iminosugars were prepared using iodine-induced intramolecular cyclization of acyclic alkenylamines as key step.
- Wang, Haibo,Pan, Yang,Tang, Qin,Zou, Wei,Shao, Huawu
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supporting information
p. 73 - 75
(2017/10/26)
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- Synthesis and antimicrobial evaluation of amino sugar-based naphthoquinones and isoquinoline-5,8-diones and their halogenated compounds
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Antibiotic resistance has emerged as a serious global public health problem and lately very few antibiotics have been discovered and introduced into clinical practice. Therefore, there is an urgent need for the development of antibacterial compounds with new mechanism of action, especially those capable of evading known resistance mechanisms. In this work two series of glycoconjugate and non-glycoconjugate amino compounds derived from of isoquinoline-5,8-dione and 1,4-naphthoquinone and their halogenated derivatives were synthesized and evaluated for antimicrobial activity against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228, S. simulans ATCC 27851) and Gram-negative bacteria (E. coli ATCC 25922, Proteus mirabilis ATCC 15290, K. pneumoniae ATCC 4352 and P. aeruginosa ATCC 27853) strains of clinical importance. This study revealed that glycoconjugate compounds derived from halogeno-substituted naphthoquinones were more active against Gram-negative strains, which cause infections whose treatment is even more difficult, according to the literature. These molecules were also more active than isoquinoline-5,8-dione analogues with minimum inhibitory concentration (MIC = 4–32 μg/mL) within Clinical and Laboratory Standard Institute MIC values (CLSI 0.08–256 μg/mL). Interestingly the minimal bactericidal concentration (MBC) values of the most active compounds were equal to MIC classifying them as bactericidal agents against Gram-negative bacteria. Sixteen compounds among eighteen carbohydrate-based naphthoquinones tested showed no hemolytic effects on health human erythrocytes whereas more susceptibility to hemolytic cleavage was observed when using non-glycoconjugate amino compounds. In silico Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) evaluation also pointed out that these compounds are potential for oral administration with low side effects. In general, this study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials more effective against Gram-negative bacteria.
- Dias, Flaviana R.F.,Novais, Juliana S.,Devillart, Talita A. do Nascimento Santos,da Silva, Wanderson Amaral,Ferreira, Matheus O.,Loureiro, Raquel de S.,Campos, Vinícius R.,Ferreira, Vitor F.,de Souza, Maria C.B.V.,Castro, Helena C.,Cunha, Anna C.
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- A Green and Sustainable Route to Carbohydrate Vinyl Ethers for Accessing Bioinspired Materials with a Unique Microspherical Morphology
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Synthesizing chemicals and materials from renewable sources is one of the main aims of modern science. Carbohydrates represent excellent renewable natural raw materials that are ecofriendly, inexpensive, and biologically compatible. A green procedure has been developed for the vinylation of carbohydrates by using readily available calcium carbide. Various carbohydrates were utilized as starting materials, resulting in mono-, di-, and tetravinyl ethers in high to excellent yields (81–92 %). The synthesized biobased vinyl ethers were utilized as monomers in free radical and cationic polymerizations. A unique combination of a smooth surface and intrinsic microcompartments was achieved in the synthesized materials. Two types of biobased materials were prepared involving microspheres and intrinsic hollow compartments in polymers. Scanning electron microscopy with built-in ion beam cutting was applied to reveal the spatial hierarchical structures in 3D space.
- Rodygin, Konstantin S.,Werner, Irina,Ananikov, Valentine P.
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p. 292 - 298
(2017/12/26)
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- LARGE SCALE PREPARATION OF PSEUDO-TRISACCHARIDE AMINOGLYCOSIDES AND OF INTERMEDIATES THEREOF
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Synthetic pathways for preparing pseudo-trisaccharide aminoglycoside compounds represented by Formula I or Ia as defined in the specification and donor and acceptor compounds useful for preparing such compounds are provided. A process of stereoselectively preparing compounds represented by Formula III as defined in the specification, while avoiding chromatographic separation of stereoisomers are also provided. Compounds prepared by the described processes and uses thereof are also provided.
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Page/Page column 62; 63
(2018/10/19)
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- Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
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Transient receptor potential melastatin-2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5′-diphosphoribose analogues were synthesized, and their activities and selectivity were evaluated. Whole-cell patch-clamp recordings were employed for screen and evaluation of synthesized compounds. Two compounds, 7i and 8a, were identified as TRPM2 inhibitors with IC50 of 5.7 and 5.4?μm, respectively. Both 7i and 8a inhibited TRPM2 current without affecting TRPM7, TRPM8, TRPV1 and TRPV3. These two TRPM2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM2 channel as a drug target, and the summarized structure–activity relationship (SAR) may also provide insights into further improving existing inhibitors as potential lead compounds.
- Luo, Xiao,Li, Meng,Zhan, Kaiyu,Yang, Wei,Zhang, Lihe,Wang, KeWei,Yu, Peilin,Zhang, Liangren
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p. 552 - 566
(2017/11/21)
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- In situ characterization of advanced glycation end products (AGEs) in collagen and model extracellular matrix by solid state NMR
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Non-enzymatic glycation of extracellular matrix with (U-13C5)-d-ribose-5-phosphate (R5P), enables in situ 2D ssNMR identification of many deleterious protein modifications and crosslinks, including previously unreported oxalamido and
- Li,Rajan,Wong,Reid,Duer,Somovilla,Martinez-Saez,Bernardes,Hayward,Shanahan
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supporting information
p. 13316 - 13319
(2017/12/26)
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- Protecting group-free use of alcohols as carbon electrophiles in atom efficient aluminium triflate-catalysed dehydrative nucleophilic displacement reactions
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Benzylic and allylic alcohols are rendered electrophilic without chemical modification by the use of aluminium triflate as catalyst. The reaction succeeds with alcohol, thiol, carbon and nitrogen nucleophiles. When phenols are employed as nucleophiles, C-alkylation ensues. An advanced application of the method is demonstrated in the synthesis of 2H-chromenes and their N and S analogues.
- Cullen, Adam,Muller, Alfred J.,Williams, D. Bradley G.
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p. 42168 - 42171
(2017/09/11)
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- Method for preparing ticagrelor key intermediate
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The invention relates to a chemical synthesis method of ticagrelor key intermediate 2-[[(3aR, 4S, 6R, 6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxolane-4-yl] oxy]ethanol (a key intermediate A). The method comprises the following steps: taking D-ribose as a raw material, and carrying out ten chemical reaction steps of 1-locus methylation and 2,3-loci isopropylidene protection, 4-locus derivatization, iodination, furan ring-opening, hydroxylamine reaction, palladium on carbon catalytic hydrogenation, amino Cbz protection, hydroxy protection, sodium borohydride reduction ester, Cbz removal protection and the like, thereby obtaining the key intermediate A. The raw materials are cheap and readily available, the preparation process is high in operability, steps of optical resolution, chiral induction and the like are avoided, the total yield is relatively high, and the product quality is better; particularly due to the use of sodium borohydride reduction ester, the preparation cost of ticagrelor is greatly reduced; and the method is suitable for large-scale industrial production.
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Paragraph 0017; 0040
(2017/02/17)
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- Synthesis of l -Ribose from d -Ribose by a Stereoconversion through Sequential Lactonization as the Key Transformation
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l -Ribose, a key precursor of various l -nucleosides can only be synthesized from other sugars or other non-sugar precursors. Herein, the study involves the synthesis of naturally rare l -ribose from readily available d -ribose. Though, many synthetic strategies are developed to meet the increasing demands of l -ribose, seeking innovation, a synthesis employing sequential lactonization as the key transformation was explored. This novel conversion involves protection, oxidation, sequential lactonization, reduction with DIBAL-H, and deprotection..
- Ban, Jaeyoung,Shabbir, Saira,Lim, Minkyung,Lee, Byunghoon,Rhee, Hakjune
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p. 4299 - 4302
(2017/09/12)
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- Synthesis of Nucleosides through Direct Glycosylation of Nucleobases with 5-O-Monoprotected or 5-Modified Ribose: Improved Protocol, Scope, and Mechanism
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Simplifying access to synthetic nucleosides is of interest due to their widespread use as biochemical or anticancer and antiviral agents. Herein, a direct stereoselective method to access an expansive range of both natural and synthetic nucleosides up to a gram scale, through direct glycosylation of nucleobases with 5-O-tritylribose and other C5-modified ribose derivatives, is discussed in detail. The reaction proceeds through nucleophilic epoxide ring opening of an in situ formed 1,2-anhydrosugar (termed “anhydrose”) under modified Mitsunobu reaction conditions. The scope of the reaction in the synthesis of diverse nucleosides and other 1-substituted riboside derivatives is described. In addition, a mechanistic insight into the formation of this key glycosyl donor intermediate is provided.
- Downey, A. Michael,Pohl, Radek,Roithová, Jana,Hocek, Michal
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supporting information
p. 3910 - 3917
(2017/03/27)
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- South (S)- and north (N)-methanocarba-7-deazaadenosine analogues as inhibitors of human adenosine kinase
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Adenosine kinase (AdK) inhibitors raise endogenous adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. On the basis of the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3.1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5′-Hydroxy (34, MRS4202 (S); 55, MRS4380 (N)) and 5′-deoxy 38a (MRS4203 (S)) analogues, containing 7- and N6-NH phenyl groups in 7-deazaadenine, robustly inhibited AdK activity (IC50 ～ 100 nM), while the 5′-hydroxy derivative 30 lacking the phenyl substituents was weak. Docking in the hAdK X-ray structure and MD simulation suggested a mode of binding similar to 5′-deoxy-5-iodotubercidin and other known inhibitors. Thus, a structure-based design approach for further potency enhancement is possible. The potent AdK inhibitors in this study are ready to be further tested in animal models of epilepsy.
- Toti, Kiran S.,Osborne, Danielle,Ciancetta, Antonella,Boison, Detlev,Jacobson, Kenneth A.
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supporting information
p. 6860 - 6877
(2016/08/05)
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- Identification of a cytotoxic molecule in heat-modified citrus pectin
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Modified forms of citrus pectin possess anticancer properties. However, their mechanism of action and the structural features involved remain unclear. Here, we showed that citrus pectin modified by heat treatment displayed cytotoxic effects in cancer cells. A fractionation approach was used aiming to identify active molecules. Dialysis and ethanol precipitation followed by HPLC analysis evidenced that most of the activity was related to molecules with molecular weight corresponding to low degree of polymerization oligogalacturonic acid. Heat-treatment of galacturonic acid also generated cytotoxic molecules. Furthermore, heat-modified galacturonic acid and heat-fragmented pectin contained the same molecule that induced cell death when isolated by HPLC separation. Mass spectrometry analyses revealed that 4,5-dihydroxy-2-cyclopenten-1-one was one cytotoxic molecule present in heat-treated pectin. Finally, we synthesized the enantiopure (4R,5R)-4,5-dihydroxy-2-cyclopenten-1-one and demonstrated that this molecule was cytotoxic and induced a similar pattern of apoptotic-like features than heat-modified pectin.
- Leclere, Lionel,Fransolet, Maude,Cambier, Pierre,El Bkassiny, Sandy,Tikad, Abdellatif,Dieu, Marc,Vincent, Stéphane P.,Van Cutsem, Pierre,Michiels, Carine
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- METHOD FOR PRODUCING THIOLANE SKELETON-TYPE GLYCOCONJUGATE, AND THIOLANE SKELETON-TYPE GLYCOCONJUGATE
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There is provided a production method of a compound represented by the following formula (II) through a step of reacting a compound represented by the following General Formula (I) with a sulfur compound. In General Formulas (I) and (II), R1 represents a hydrogen atom or an acyl group, R2 represents a hydrogen atom, a fluorine atom, an acyloxy group, an arylmethyloxy group, an allyloxy group, an arylmethyloxycarbonyloxy group, or an allyloxycarbonyloxy group, R3 represents a hydrogen atom or an acyloxy group, R5 represents an alkyl group or an aryl group, and X represents a leaving group. Here, in a case where R2 is a fluorine atom, an acyloxy group, an arylmethyloxy group, an allyloxy group, an arylmethyloxycarbonyloxy group, or an allyloxycarbonyloxy group, R3 is an acyloxy group.
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Paragraph 0502-0505
(2016/12/26)
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- Capecitabine and wherein the intermediate preparation method
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The invention discloses a preparation method of capecitabine. The method comprises the following steps: based on D-ribose serving as a starting raw material, carrying out hydroxyl protection, 5-site tosylation, iodine substitution, hypophosphorous acid deiodination and acetylation so as to obtain the key intermediate 12,3-tri-O-acetyl-5-deoxy-beta-D-ribofuranose; carrying out glycosylation on the key intermediate and 5-fluorocytosine; and finally, carrying out N-4 site acylation and deprotection so as to obtain the capecitabine. In the method, a metal catalyst dose not need to be used for participating in reaction, the reaction condition is mild, and the yield is high, thus the method is economical and effective as well as suitable for industrial production on a large scale.
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-
Paragraph 0035; 0036; 0037
(2017/02/09)
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- Diversity-Oriented Synthesis of cis -3,4-Dihydroxylated Piperidine and Its Higher Saturated and Unsaturated Homologues from d -Ribose and Their Glycosidase-Inhibition Study 1
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The synthesis of six-, seven-, and eight-membered cis-dihydroxy azacycles has been accomplished from d-ribose using Vasella reductive amination as a key step and utilization of hydroboration-oxidation, Mitsunobu reaction, and ring-closing metathesis (RCM) reactions in a facile manner. These homologous dihydroxylated heterocyclic scaffolds were subjected to the glycosidase inhibition assays. However, only a moderate inhibitory activity for three out of five compounds was observed against α-glucosidases with a high degree of selectivity.
- Ajay, Sama,Arora, Inderpreet,Saidhareddy, Puli,Shaw, Arun K.
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p. 2721 - 2725
(2016/11/30)
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- N2-glycosyl-substituted 1,2,3-triazole compound and synthesis method and application thereof
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The invention relates to an N2-glycosyl-substituted 1,2,3-triazole compound and a synthesis method and application thereof. The general structural formula of the N2-glycosyl-substituted 1,2,3-triazole compound is shown in the specification, wherein R1 indicates H atoms or halogen atoms or alkyl groups of 1-6 carbon atoms or alkoxy groups of 3-10 carbon atoms or aryl groups or heterocyclic groups or benzoyl groups or formyloxy groups or cyano groups, and R indicates hydrogen or alkyl groups or halogen atoms or nitro groups or alkoxy groups or cyano groups and is located at ortho-position, meta-position and para-position single substitution or polysubstitution of aromatic rings. The N2-glycosyl-substituted 1,2,3-triazole compound and the synthesis method and application thereof have the advantages that synthesis conditions are easy to control, the yield is high, and the cost is low; application of triazole derivatives in the fields of pesticide, medicine, food and the like is further promoted; a new way is provided for research and development of high-value utilization and modification of triazole; the compound has high inhibiting ability for alpha-glucosidase and can be further developed into medicine used for treating or assisting in treating diabetes mellitus type 2.
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Paragraph 0050; 0052; 0053
(2017/01/26)
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- Continuous fluorescence assays for reactions involving adenine
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5′-Methylthioadenosine phosphorylase (MTAP) and 5′-methylthioadenosine nucleosidase (MTAN) catalyze the phosphorolysis and hydrolysis of 5′-methylthioadenosine (MTA), respectively. Both enzymes have low KM values for their substrates. Kinetic assays for these enzymes are challenging, as the ultraviolet absorbance spectra for reactant MTA and product adenine are similar. We report a new assay using 2-amino-5′-methylthioadenosine (2AMTA) as an alternative substrate for MTAP and MTAN enzymes. Hydrolysis or phosphorolysis of 2AMTA forms 2,6-diaminopurine, a fluorescent and easily quantitated product. We kinetically characterize 2AMTA with human MTAP, bacterial MTANs and use 2,6-diaminopurine as a fluorescent substrate for yeast adenine phosphoribosyltransferase. 2AMTA was used as the substrate to kinetically characterize the dissociation constants for three-transition-state analogue inhibitors of MTAP and MTAN. Kinetic values obtained from continuous fluorescent assays with MTA were in good agreement with previously measured literature values, but gave smaller experimental errors. Chemical synthesis from ribose and 2,6-dichloropurine provided crystalline 2AMTA as the oxalate salt. Chemo-enzymatic synthesis from ribose and 2,6-diaminopurine produced 2-amino-S-adenosylmethionine for hydrolytic conversion to 2AMTA. Interaction of 2AMTA with human MTAP was also characterized by pre-steady-state kinetics and by analysis of the crystal structure in a complex with sulfate as a catalytically inert analogue of phosphate. This assay is suitable for inhibitor screening by detection of fluorescent product, for quantitative analysis of hits by rapid and accurate measurement of inhibition constants in continuous assays, and pre-steady-state kinetic analysis of the target enzymes.
- Firestone, Ross,Cameron, Scott,Tyler, Peter,Ducati, Rodrigo,Spitz, Adam,Schramm, Vern
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p. 11860 - 11867
(2018/04/25)
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- Safe and Alternate Process for the Reductions of Methanesulfonates: Application in the Synthesis of 1,2,3-Triacetyl-5-deoxy-d-ribofuranoside
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Diethylene glycol dimethyl ether, diglyme, and 1,2-bis(2-methoxyethoxy)ethane, triglyme, are found to be suitable and safe alternate solvents to DMSO for the reduction of methanesulfonate in sodium borohydride. Addition of anhydrous lithium chloride led to the complete reduction of methanesulfonate esters to the corresponding alkanes in the presence of sodium borohydride in these solvents (diglyme and triglyme). This protocol is useful in the preparation of 1,2,3-triacetyl-5-deoxy-d-ribofuranoside, 7, a key intermediate of Capecitabine, 1, on the commercial scale.
- Mekala, Nagaraju,Moturu, Murthy V.R.K.,Dammalapati, Rao V.L.N.,Parimi, Atchuta R.
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p. 609 - 614
(2016/04/04)
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- Efficient O-Functionalization of Carbohydrates with Electrophilic Reagents
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Novel methodology for O-functionalization of carbohydrate derivatives has been established using bench-stable and easily prepared iodonium(III) reagents. Both electron-withdrawing and electron-donating aryl groups were introduced under ambient conditions and without precautions to exclude air or moisture. Furthermore, the approach was extended both to full arylation of cyclodextrin, and to trifluoroethylation of carbohydrate derivatives. This is the first general approach to introduce traditionally non-electrophilic groups into any of the OH groups around the sugar backbone. The methodology will be useful both in synthetic organic chemistry and biochemistry, as important functional groups can be incorporated under simple and robust reaction conditions in a fast and efficient manner.
- Tolnai, Gergely L.,Nilsson, Ulf J.,Olofsson, Berit
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supporting information
p. 11226 - 11230
(2016/10/13)
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- Synthesis and biological activity of reversed pyrimidine nucleosides
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An efficient approach to reversed nucleosides which enables their synthesis in gram quantities is described. N-1′-Pyrimidine reversed nucleosides were prepared by treating of the sodium salt of pyrimidine bases with protected 5-tosyl ribose. Additionally, N-1′,N-3′-disubstituted reversed nucleosides were isolated in the condensation reactions with the 5-halogen pyrimidines. Using the Sonogashira coupling of 5′-iodouracil reversed nucleoside with ethynyltrimethyl silane gave 5′-ethynyl derivative which was further transformed into 5′-acetyl reversed nucleoside. Biological activity of deprotected reversed nucleosides was validated on the panel of six human carcinoma cell lines (HeLa, MIAPaCa2, Hep2, NCI-H358, CaCo-2, and HT-29). 5′-Iodouracil derivative displayed moderate growth inhibition activity against human colon carcinoma (CaCo-2) cells.
- ?upan?i?, Nata?a,Ban, ?eljka,Mati?, Josipa,Safti?, Dijana,Glava?-Obrovac, Ljubica,?ini?, Biserka
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- Synthesis, characterization, cytotoxic and antitubercular activities of new gold(I) and gold(III) complexes containing ligands derived from carbohydrates
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Novel gold(I) and gold(III) complexes containing derivatives of d-galactose, d-ribose and d-glucono-1,5-lactone as ligands were synthesized and characterized by IR, 1H, and 13C NMR, high resolution mass spectra and cyclic voltammetry. The compounds were evaluated in vitro for their cytotoxicity against three types of tumor cells: cervical carcinoma (HeLa) breast adenocarcinoma (MCF-7) and glioblastoma (MO59J) and one non-tumor cell line: human lung fibroblasts (GM07492A). Their antitubercular activity was evaluated as well expressed as the minimum inhibitory concentration (MIC90) in μg/mL. In general, the gold(I) complexes were more active than gold(III) complexes, for example, the gold(I) complex (1) was about 8.8 times and 7.6 times more cytotoxic than gold(III) complex (8) in MO59J and MCF-7 cells, respectively. Ribose and alkyl phosphine derivative complexes were more active than galactose and aryl phosphine complexes. The presence of a thiazolidine ring did not improve the cytotoxicity. The study of the cytotoxic activity revealed effective antitumor activities for the gold(I) complexes, being more active than cisplatin in all the tested tumor cell lines. Gold(I) compounds (1), (2), (3), (4) and (6) exhibited relevant antitubercular activity even when compared with first line drugs such as rifampicin.
- Chaves, Joana Darc Souza,Damasceno, Jaqueline Lopes,Paula, Marcela Cristina Ferreira,De Oliveira, Pollyanna Francielli,Azevedo, Gustavo Chevitarese,Matos, Renato Camargo,Louren?o, Maria Cristina S.,Tavares, Denise Crispim,Silva, Heveline,Fontes, Ana Paula Soares,De Almeida, Mauro Vieira
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p. 845 - 860
(2015/09/29)
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- Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development
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Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed. (Chemical Equation Presented).
- Shaw, Scott A.,Balasubramanian, Balu,Bonacorsi, Samuel,Cortes, Janet Caceres,Cao, Kevin,Chen, Bang-Chi,Dai, Jun,Decicco, Carl,Goswami, Animesh,Guo, Zhiwei,Hanson, Ronald,Humphreys, W. Griffith,Lam, Patrick Y. S.,Li, Wenying,Mathur, Arvind,Maxwell, Brad D.,Michaudel, Quentin,Peng, Li,Pudzianowski, Andrew,Qiu, Feng,Su, Shun,Sun, Dawn,Tymiak, Adrienne A.,Vokits, Benjamin P.,Wang, Bei,Wexler, Ruth,Wu, Dauh-Rurng,Zhang, Yingru,Zhao, Rulin,Baran, Phil S.
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p. 7019 - 7032
(2015/07/27)
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- Synthesis of a new class of naphthoquinone glycoconjugates and evaluation of their potential as antitumoral agents
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A novel series of carbohydrate-based naphthoquinones was synthesized and evaluated for cytotoxicity against different cancer cell lines. The compounds derived from 5-hydroxy-1,4-naphthoquinone (juglone) showed better cytotoxicity profiles against HCT-116, A-549 and MDA-MB 435 human cancer cells than the parent compound. The results suggest that the hydroxyl group on the aromatic ring increased the pro-oxidant activity of these new naphthoquinone derivatives. Furthermore, two derivatives were found to be more active against melanoma cells (MDA-MB435) than the clinically useful anticancer agent doxorubicin, and none of the compounds caused mouse erythrocyte lysis.
- Campos, Vinicius R.,Cunha, Anna C.,Silva, Wanderson A.,Ferreira, Vitor F.,Santos De Sousa, Carla,Fernandes, Patrícia D.,Moreira, Vinícius N.,Da Rocha, David R.,Dias, Flaviana R. F.,Montenegro, Raquel C.,De Souza, Maria C. B. V.,Boechat, Fernanda Da C. S.,Franco, Caroline F. J.,Resende, Jackson A. L. C.
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p. 96222 - 96229
(2015/11/24)
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- MODIFIED 2' AND 3'-NUCLEOSIDE PRODRUGS FOR TREATING FLAVIVIRIDAE VIRUS INFECTIONS
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PROBLEM TO BE SOLVED: To provide 2' and/or 3' prodrugs of 1', 2', 3', or 4'-branched nucleosides for treating flaviviridae virus infections. SOLUTION: The invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound. The compound is used for preventing or treating Flaviviridae virus infection and other associated conditions by administering independently, or in combination or alternation with an antiviral drug, such as interferon. [R1-R3 are H or the like; X1 and X2 are H or an alkyl group or the like; Y1 and Y3 are an alkyl group or the like.] COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0443; 0444
(2016/12/01)
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- Replacement of water molecules in a phosphate binding site by furanoside-appended lin-benzoguanine ligands of tRNA-guanine transglycosylase (TGT)
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The enzyme tRNA-guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure-based design for this enzyme is the filling of the polar ribose-34 pocket. Herein, we describe a novel series of ligands consisting of furanoside-appended lin-benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe.The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose-34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X-ray co-crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose-34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster.
- Barandun, Luzi J.,Giroud, Maude,Grünenfelder, Claudio,Schweizer, W. Bernd,Bernet, Bruno,Diederich, Franois,Ehrmann, Frederik R.,Immekus, Florian,Betz, Michael,Heine, Andreas,Klebe, Gerhard,Zimmerli, Daniel
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supporting information
p. 126 - 135
(2015/02/18)
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- Highly Substituted Cyclopentane-CMP Conjugates as Potent Sialyltransferase Inhibitors
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Sialylconjugates on cell surfaces are involved in many biological events such as cellular recognition, signal transduction, and immune response. It has been reported that aberrant sialylation at the nonreducing end of glycoconjugates and overexpression of sialyltransferases (STs) in cells are correlated with the malignance, invasion, and metastasis of tumors. Therefore, inhibitors of STs would provide valuable leads for the discovery of antitumor drugs. On the basis of the transition state of the enzyme-catalyzed sialylation reaction, we proposed that the cyclopentane skeleton in its two puckered conformations might mimic the planar structure of the donor (CMP-Neu5Ac) in the transition state. A series of cyclopentane-containing compounds were designed and synthesized by coupling different cyclopentane α-hydroxyphosphonates with cytidine phosphoramidite. Their inhibitory activities against recombinant human ST6Gal-I were assayed, and a potent inhibitor 48l with a Ki of 0.028 ± 0.006 μM was identified. The results show that the cyclopentanoid-type compounds could become a new type of sialyltransferase inhibitors as biological probes or drug leads.
- Li, Wenming,Niu, Youhong,Xiong, De-Cai,Cao, Xiaoping,Ye, Xin-Shan
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supporting information
p. 7972 - 7990
(2015/11/09)
-
- Synthesis of Dimeric ADP-Ribose and Its Structure with Human Poly(ADP-ribose) Glycohydrolase
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Poly(ADP-ribosyl)ation is a common post-translational modification that mediates a wide variety of cellular processes including DNA damage repair, chromatin regulation, transcription, and apoptosis. The difficulty associated with accessing poly(ADP-ribose) (PAR) in a homogeneous form has been an impediment to understanding the interactions of PAR with poly(ADP-ribose) glycohydrolase (PARG) and other binding proteins. Here we describe the chemical synthesis of the ADP-ribose dimer, and we use this compound to obtain the first human PARG substrate-enzyme cocrystal structure. Chemical synthesis of PAR is an attractive alternative to traditional enzymatic synthesis and fractionation, allowing access to products such as dimeric ADP-ribose, which has been detected but never isolated from natural sources. Additionally, we describe the synthesis of an alkynylated dimer and demonstrate that this compound can be used to synthesize PAR probes including biotin and fluorophore-labeled compounds. The fluorescently labeled ADP-ribose dimer was then utilized in a general fluorescence polarization-based PAR-protein binding assay. Finally, we use intermediates of our synthesis to access various PAR fragments, and evaluation of these compounds as substrates for PARG reveals the minimal features for substrate recognition and enzymatic cleavage. Homogeneous PAR oligomers and unnatural variants produced from chemical synthesis will allow for further detailed structural and biochemical studies on the interaction of PAR with its many protein binding partners. (Chemical Equation Presented).
- Lambrecht, Michael J.,Brichacek, Matthew,Barkauskaite, Eva,Ariza, Antonio,Ahel, Ivan,Hergenrother, Paul J.
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supporting information
p. 3558 - 3564
(2015/03/30)
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- Iodoetherification of conformationally restricted dienyl alcohols: Unexpected formation of oxocenes by 8-endo-mode oxacyclizations
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Iodine-promoted oxacyclizations of a family of conformationally restricted dienyl alcohols consistently afford oxocenes, arising from 8-endo-mode cyclizations.
- Stoltz, Kristen L.,Alba, Andrea-Nekane R.,McDonald, Frank E.,Wieliczko, Marika B.,Bacsa, John
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p. 1519 - 1526
(2016/10/12)
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- Analogues of the natural product sinefungin as inhibitors of EHMT1 and EHMT2
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A series of analogues of the natural product sinefungin lacking the amino acid moiety was synthesized and probed for their ability to inhibit EHMT1 and EHMT2. This study led to inhibitors 3b and 4d of methyltransferase activity of EHMT1 and EHMT2 and it demonstrates that such analogues constitute an interesting scaffold to develop selective methyltransferase inhibitors. Surprisingly, the inhibition was not competitive toward AdoMet.
- Devkota, Kanchan,Lohse, Brian,Liu, Qing,Wang, Ming-Wei,Staerk, Dan,Berthelsen, Jens,Clausen, Rasmus Praetorius
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p. 293 - 297
(2014/05/06)
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